PROJECT SUMMARY/ABSTRACT Hantaviruses are the etiological agents of hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS). There are no FDA-approved medical countermeasures to prevent or treat these unpredictable zoonotic diseases. Recently, clinicians in Chile demonstrated that convalescent plasma from HPS survivors provided a clinical benefit in HPS patients in a compassionate-use study. However, the paucity of available human plasma containing high-titer neutralizing antibodies against hantaviruses, and other drawbacks to the use of human plasma derived products, makes the use of convalescent plasma as an anti- hantavirus product untenable. We propose to further develop a potent polyclonal antibody anti-hantavirus product using transchromosomal (Tc) bovine technology. This technology overcomes the significant challenges presented by therapies consisting of polyclonal antibodies obtained from human plasma donors or animal sources. SAB?s diversitAb? platform technology uses cattle carrying knockouts of key bovine antibody heavy light chains genes, and the addition of a Human Artificial Chromosome containing the entire human heavy chain locus and the entire human kappa light chain locus. As partners, SAB and the US Army Medical Research Institute of Infectious Diseases (USAMRIID) have already demonstrated that fully-human IgG purified from plasma collected from the Tc bovines immunized with hantavirus DNA vaccines has potent neutralizing antibody activity in vitro, and is protective in vivo (i.e., Syrian hamster models of lethal HPS disease). Here, we will use our existing hantavirus DNA vaccines and diversitAb? platform technology to produce a pan-hantavirus polyclonal antibody product under cGMP. We will conduct in vitro neutralization assays to measure potency, and in vivo efficacy studies using established Syrian hamster models of infection and disease. In addition, we will subject the candidate product to stability testing, human tissue cross reactivity testing, pharmacokinetic analysis in nonhuman primates, and a GLP preclinical toxicity study in rabbits. Our goal is to advance a lead candidate anti-hantavirus polyclonal antibody immunotherapeutic product through preclinical testing. At the conclusion of these IND-enabling studies, this candidate anti-hantavirus product will be ready for a Phase 1 clinical trial.